Ischaemic and metabolic treatment of hepatic tumours

For treatment of malignancies, physical and metabolic differences between tumour cells and host cells have guided the development of new approaches. In this review, two new approaches to be used in the treatment of liver malignancies are outlined: ischaemic therapy and interferences with the glucose metabolism. Ischaemic therapy of liver malignancies has been used in different forms during the last 20 years: from ligation of the hepatic artery, embolization of the arterial tree, transient occlusion of the hepatic artery to the present day use of temporary, intermittent, transient hepatic arterial occlusion. The beneficial effect of ischaemic therapy on malignancies is supposed to depend on oxygen and nutritional deficiency, formation of oxygen-derived free radicals and loss of function in cellular enzymes. The tumour cells seem thereby to be more sensitive than the host cells. Also, ischaemia might potentiate the effect of cytotoxic drugs. Intereferencies with glucose metabolism might be directed either towards the exaggerated tumour glycolysis, for example by glucose analogues like 2-deoxy-glucose, or towards the exaggerated host gluconeogenesis, for example by hydrazine sulphate. These treatments result in reduction of the glucose availability in the intracellular glucose metabolism in the tumour cells and have experimentally been demonstrated to be correlated to reduced tumour growth. It is concluded that both these approaches, ischaemic therapy and manipulations with the glucose metabolism, seem promising for the future. What is needed now is research to clarify the mechanisms behind the effects, to establish their full consequences, and to identify the clinical use of these treatments and their possible combinations

Pharmacokinetics of human leptin in mice and rhesus monkeys.

ObjectiveThe pharmacokinetic characteristics of human leptin were examined in rhesus monkeys and in C57BL/6J mice fed a normal chow or a high-fat diet.DesignFor the monkey study, in nine rhesus monkeys (body weight 12.4 +/- 2.4 kg; mean +/- s.d.), recombinant met-human leptin was injected intravenously or subcutaneously (1 mg/kg). For the mouse study, after 6 months of feeding C57BL/6J mice a high-fat diet (body weight 32.9 +/- 3.6 g; n = 8) or a control diet (24.5 +/- 1.2 g; n = 6), recombinant met-human leptin was administered intraperitoneally (10 microg/g). Blood samples were collected for leptin measurement at specific time points after leptin administration.MeasurementsPlasma leptin concentrations were determined by radioimmunoassay and pharmacokinetic analysis was performed.ResultsDisposition of human leptin in rhesus monkeys was biphasic following intravenous administration, with a terminal phase half-life of 96.4 +/- 16.5 min and clearance of 1.8 +/- 0.2 ml/min/kg. Subcutaneously administered leptin was absorbed slowly, perhaps by a zero-order process as leptin levels appeared to plateau and remained elevated throughout the 8 h sampling period. In C57BL/6J mice, the absorption and elimination of human leptin were both first-order following intraperitoneal administration. Pharmacokinetic parameters did not differ between normal-weight mice fed a chow diet and obese mice fed a high-fat diet. The elimination half-life was 47.0 +/- 26.4 min in mice fed a high-fat diet and 49.5 +/- 12.0 min in mice fed a control diet.ConclusionThe kinetics of leptin in rhesus monkeys were biphasic and clearance was similar to values previously reported in humans. The estimated half-life was 96.4 min in rhesus monkeys and 49.5 min in normal weight mice. The was no difference in leptin kinetics between high-fat fed and control mice, suggesting that the increased baseline leptin levels in the obese mice are due to increased leptin production and secretion

Subtotal pancreatectomy for cancer: closure of the pancreatic remnant with staplers

This paper presents a 2-year series of 26 consecutive pancreatectomies for periampullary cancer where the pancreatic tail was closed with a stapler in order to avoid complications related to a pancreatico-digestive anastomosis. The follow-up period was 14 months or more. Seven patients developed operative complications. Pancreatic fistulas developed in 3 patients. The fistulas closed spontaneously in 2 of the patients after 2-4 months. Intraabdominal abscesses developed in 4 patients and required surgical drainage. In 1 of these patients, the abscess eroded a large vessel with a fatal outcome resulting in an operative mortality rate of 3.8%. A transient postoperative gastric stasis was observed in seven patients. Postoperative hospital median stay was 27 days (range 10-83 days). Eighteen patients have died after 4-30 months in recurrent disease and seven patients are alive after a follow-up period of 15-29 months. Pancreatic endocrine function seemed well preserved; diabetes mellitus has developed in only one patient. In conclusion, it appears that subtotal pancreatectomy with closure of the pancreatic remnant with staples gives a low morbidity and mortality. Although the conclusion should be tempered by the small number of patients, the results justify continued evaluation of this technique with long-term follow-up

GLP-1 released to the mesenteric lymph duct in mice: Effects of glucose and fat.

Using a newly developed in vivo model measuring glucagon-like peptide-1 (GLP-1) in gut lymphatics in mice, we quantified GLP-1 secretion in vivo after glucose versus fat ingestion with and without concomitant DPP-4 inhibition. The mesenteric lymphatic duct was cannulated in anesthetized C57BL6/J mice and lymph was collected in 30min intervals. Glucose or fat emulsion (Intralipid(R)) (0.03, 0.1 or 0.3kcal) with or without DPP-4-inhibition (NVP DPP728; 10μmol/kg) was administered by gastric gavage. Basal intact GLP-1 levels were 0.37±0.04pmol/l (n=61) in lymph compared to 0.07±0.03 in plasma (n=6; P=0.04) and basal DPP-4 activity was 4.7±0.3pmol/min/μl in lymph (n=23) compared to 22.3±0.9pmol/min/μl in plasma (n=8; P<0.001). Lymph flow increased from 1.2±0.1μl/min to 2.3±02μl/min at 30min after glucose and fat administration, with no difference between type of challenge or dose (n=81). Lymph GLP-1 levels increased calorie-dependently after both glucose and fat but with different time courses in that glucose induced a transient increase which had returned to baseline after 90min whereas the lipid induced a sustained increase which was still elevated above baseline after 210min. Lymph GLP-1 appearance during 210min was two to three-fold higher after glucose (7.4±2.3fmol at 0.3kcal) than after isocaloric fat (2.9±0.8fmol at 0.3kcal; P<0.001). The slope between caloric load and lymph GLP-1 appearance was, however, identical after glucose and fat. We conclude that lymph GLP-1 is higher than plasma GLP-1 whereas lymph DPP-4 activity is lower than plasma DPP-4 activity and that both glucose and fat clearly stimulate GLP-1 secretion calorie-dependently in vivo but with different time courses

Study on administration of 1,5-anhydro-D-fructose in C57BL/6J mice challenged with high-fat diet

1,5-Anhydro-D-fructose (AF) is a mono-saccharide directly formed from starch and glycogen by the action of α-1,4-glucan lyase (EC 4.2.2.13). Our previous study has indicated that AF increases glucose tolerance and insulin secretion in NMRI mice after administration through a gastric gavage in a single dose at 150 mg per mouse. In this study, we used high-fat feeding of C57BL/6J mice to examine the influence of long-term administration of AF on glucose-stimulated insulin secretion in vivo and in vitro. We found that 8-weeks of high-fat feeding increased body weight, fasting blood glucose and insulin levels in C57BL/6J mice when compared to mice fed normal diet. Impaired glucose tolerance was also observed in mice receiving 8-weeks of high-fat diet. In contrast, AF (1.5 g/kg/day), administered through drinking water for 8-weeks, did not affect body weight or food and water intake in mice fed either the high-fat or normal diet. There was no difference in basal blood glucose or insulin levels between AF-treated and control group. Oral glucose tolerance test (OGTT) showed that AF did not affect glucose-stimulated insulin secretion in mice. In in vitro studies with isolated islets, AF did not influence glucose-stimulated insulin secretion in mice receiving either high-fat or normal diet. We therefore conclude that when given through drinking water for 8 weeks at 1.5 g/kg/day, AF has no effect on glucose-stimulated insulin secretion in C57BL/6J mice challenged with a high-fat diet